p53 is a tumor suppresser protein that plays a central role in protection against development of cancer. It guards cellular integrity and prevents the propagation of permanently damaged clones of cells by the induction of growth arrest or apoptosis. At the molecular level, p53 is a transcription factor that can activate a panel of genes implicated in the regulation of cell cycle and apoptosis. p53 is a potent cell cycle inhibitor which is tightly regulated by MDM2 at the cellular level. MDM2 and p53 form a feedback control loop. MDM2 can bind p53 and inhibit its ability to transactivate p53-regulated genes. In addition, MDM2 mediates the ubiquitin-dependent degradation of p53. p53 can activate the expression of the MDM2 gene, thus raising the cellular level of MDM2 protein. This feedback control loop insures that both MDM2 and p53 are kept at a low level in normal proliferating cells. MDM2 is also a cofactor for E2F, which plays a central role in cell cycle regulation.
The ratio of MDM2 to p53 (E2F) is dysregulated in many cancers. Frequently occurring molecular defects in the p16INK4/p19ARF locus, for instance, have been shown to affect MDM2 protein degradation. Inhibition of MDM2-p53 interaction in tumor cells with wild-type p53 should lead to accumulation of p53, cell cycle arrest and/or apoptosis. MDM2 antagonists, therefore, can offer a novel approach to cancer therapy as single agents or in combination with a broad spectrum of other antitumor therapies. The feasibility of this strategy has been shown by the use of different macromolecular tools for inhibition of MDM2-p53 interaction (e.g. antibodies, antisense oligonucleotides, peptides). MDM2 also binds E2F through a conserved binding region as p53 and activates E2F-dependent transcription of cyclin A, suggesting that MDM2 antagonists might have effects in p53 mutant cells.
Wells et al. J. Org. Chem., 1972, 37, 2158-2161, report synthesis of imidazolines. Hunter et al., Can. J. Chem., 1972, Vol. 50, pgs. 669-77, report the preparation of amarine and isoamarine compounds which had previously been studied for chemiluminescence (McCapra et al. Photochem. and Photobiol. 1965, 4, 1111-1121). Zupanc et al. Bull. Soc. Chem. and Tech. (Yugoslavia) 1980-81, 27/28, 71-80, report the use of triaryl imidazolines as starting materials in the preparation of EDTA derivatives. EP 363 061 to Matsumoto reports imidazoline derivatives useful as immunomodulators. The compounds were indicated to have low toxicity. Treatment and/or prevention of rheumatoid arthritis, multiple sclerosis, systemic lupus, erythemathodes, and rheumatic fever were implicated. WO 00/78725 to Choueiry et al. report a method for making substituted amidine compounds, and indicate that imidazoline-type compounds may be useful in the treatment of diabetes or related diseases involving impaired glucose disposal.
The present invention provides at least one compound selected from a compound of formula I 
and the pharmaceutically acceptable salts and esters thereof, wherein
R is xe2x80x94Cxe2x95x90OR1,
wherein R1 is C1-C4 alkyl, xe2x80x94Cxe2x95x90CHCOOH, xe2x80x94NHCH2CH2R2, xe2x80x94N(CH2CH2OH)CH2CH2OH, xe2x80x94N(CH3)CH2CH2NCH3, xe2x80x94N(CH3)CH2CH2N(CH3)CH3, saturated 4-, 5- and 6-membered rings, saturated and unsaturated 5- and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O and being optionally substituted with a group selected from lower alkyl, xe2x80x94Cxe2x95x90Oxe2x80x94R5, xe2x80x94OH, lower alkyl substituted with hydroxy, lower alkyl substituted with xe2x80x94NH2, N-lower alkyl, xe2x80x94SO2CH3, xe2x95x90O, xe2x80x94CH2Cxe2x95x90OCH3, and 5- and 6-membered saturated rings containing at least one hetero atom selected from S, N and O,
wherein R5 is selected from H, lower alkyl, xe2x80x94NH2, xe2x80x94N-lower alkyl, lower alkyl substituted with hydroxy, and lower alkyl substituted with NH2,
wherein R2 is selected from xe2x80x94N(CH3)CH3, xe2x80x94NHCH2CH2NH2, xe2x80x94NH2, morpholinyl and piperazinyl,
X1, X2 and X3 are independently selected from xe2x80x94OH, C1-C2 alkyl, C1-C5 alkoxy, xe2x80x94Cl, xe2x80x94Br, xe2x80x94F, xe2x80x94CH2OCH3, and xe2x80x94CH2OCH2CH3,
or one of X1, X2 or X3 is H and the other two are independently selected from hydroxy, lower alkyl, lower alkoxy, Cl, Br, F, CF3 xe2x80x94CH2OCH3, xe2x80x94CH2OCH2CH3 xe2x80x94OCH2CH2R3, xe2x80x94OCH2CF3, and xe2x80x94Oxe2x80x94R4,
or one of X1, X2 or X3 is H and the other two taken together with the two carbon atoms and the bonds between them from the benzene ring to which they are substituted form a 6-membered saturated ring that contains at least one hetero atom selected from S, N, and O,
wherein R3 is selected from xe2x80x94F, xe2x80x94OCH3, xe2x80x94N(CH3)CH3, unsaturated 5-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O,
wherein R4 is a 3- to 5-membered saturated ring and
Y1 and Y2 are each independently selected from xe2x80x94Cl, xe2x80x94Br, xe2x80x94NO2, xe2x80x94Cxe2x89xa1N and xe2x80x94Cxe2x89xa1CH.
The present invention also provides at least one compound selected from a compound of formula II 
and the pharmaceutically acceptable salts and esters thereof, wherein
R is xe2x80x94Cxe2x95x90OR1,
wherein R1 is selected from C1-C4 alkyl, saturated 5- and 6-membered rings, saturated 5- and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O and being optionally substituted with a group selected from C1-C2 alkyl, C1-C3 alcohol, xe2x80x94N(CH3)CH3, and xe2x80x94Cxe2x95x90OCH3, and 5- and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N, and O,
X4 is selected from C1-C2 alkyl, C1-C5 alkoxy, xe2x80x94Cl, xe2x80x94Br, xe2x80x94F, xe2x80x94OCH2Cxe2x95x90OOQ, xe2x80x94OCH2 cyclopentyl, xe2x80x94CH2OCH2-phenyl, saturated and unsaturated 5- and 6-membered rings, saturated and unsaturated 5- and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O,
wherein Q is selected from H and lower alkyl,
Y1 and Y2 are independently selected from xe2x80x94Cl, xe2x80x94Br, xe2x80x94NO2, xe2x80x94Cxe2x89xa1N and xe2x80x94Cxe2x89xa1CH,
with the proviso that where Y1 and Y2 are both xe2x80x94Cl, and R1 is xe2x80x94CH3 or phenyl, then X4 is not xe2x80x94Cl.
The present invention provides cis-imidazolines which are small molecule inhibitors of the MDM2-p53 interaction. In cell-free and cell-based assays, compounds of the present invention are shown to inhibit the interaction of MDM2 protein with a p53-like peptide with a potency that is approximately 100 fold greater than a p53-derived peptide. In cell-based assays, these compounds demonstrate mechanistic activity. Incubation of cancer cells with wild-type p53 leads to accumulation of p53 protein, induction of p53-regulated p21 gene, and cell cycle arrest in G1 and G2 phase, resulting in potent antiproliferative activity against wild-type p53 cells in vitro. In contrast, these activities were not observed in cancer cells with mutant p53 at comparable compound concentrations. Therefore, the activity of MDM2 antagonists is likely linked to its mechanism of action. These compounds can be potent and selective anticancer agents.
The present invention provides at least one compound selected from a compound of formula I 
and the pharmaceutically acceptable salts and esters thereof, wherein
R is xe2x80x94Cxe2x95x90OR1,
wherein R1 is C1-C4 alkyl, xe2x80x94Cxe2x95x90CHCOOH, xe2x80x94NHCH2CH2R2, xe2x80x94N(CH2CH2OH)CH2CH2OH, xe2x80x94N(CH3)CH2CH2NCH3, xe2x80x94N(CH3)CH2CH2N(CH3)CH3, saturated 4-, 5- and 6-membered rings, saturated and unsaturated 5- and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O and being optionally substituted with a group selected from lower alkyl, xe2x80x94Cxe2x95x90Oxe2x80x94R5, xe2x80x94OH, lower alkyl substituted with hydroxy, lower alkyl substituted with xe2x80x94NH2, N-lower alkyl, xe2x80x94SO2CH3, xe2x95x90O, xe2x80x94CH2Cxe2x95x90OCH3, and 5- and 6-membered saturated rings containing at least one hetero atom selected from S, N and O,
wherein R5 is selected from H, lower alkyl, xe2x80x94NH2, xe2x80x94N-lower alkyl, lower alkyl substituted with hydroxy, and lower alkyl substituted with NH2,
wherein R2 is selected from xe2x80x94N(CH3)CH3, xe2x80x94NHCH2CH2NH2, xe2x80x94NH2, morpholinyl and piperazinyl,
X1, X2 and X3 are independently selected from xe2x80x94OH, C1-C2 alkyl, C1-C5 alkoxy, xe2x80x94Cl, xe2x80x94Br, xe2x80x94F, xe2x80x94CH2OCH3, and xe2x80x94CH2OCH2CH3,
or one of X1, X2 or X3 is H and the other two are independently selected from hydroxy, C1-C2 alkyl, C1-C5 alkoxy, Cl, Br, F, CF3 xe2x80x94CH2OCH3, xe2x80x94CH2OCH2CH3xe2x80x94OCH2CH2R3, xe2x80x94CH2CF3, and xe2x80x94Oxe2x80x94R4,
or one of X1, X2 or X3 is H and the other two taken together with the two carbon atoms and the bonds between them from the benzene ring to which they are substituted form a 6-membered saturated ring that contains at least one hetero atom selected from S, N, and O,
wherein R3 is selected from xe2x80x94F, xe2x80x94OCH3, xe2x80x94N(CH3)CH3, unsaturated 5-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O,
wherein R4 is a 3- to 5-membered saturated ring and
Y1 and Y2 are each independently selected from xe2x80x94Cl, xe2x80x94Br, xe2x80x94NO2, xe2x80x94Cxe2x89xa1N, and xe2x80x94Cxe2x89xa1CH.
The present invention also provides at least one compound selected from a compound of formula II 
and the pharmaceutically acceptable salts and esters thereof, wherein
R is xe2x80x94Cxe2x95x90OR1,
wherein R1 is selected from C1-C4 alkyl, saturated 5- and 6-membered rings, saturated 5- and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O and being optionally substituted with a group selected from C1-C2 alkyl, C1-C3 alcohol, xe2x80x94N(CH3)CH3, and xe2x80x94Cxe2x95x90OCH3, and 5- and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N, and O,
X4 is selected from C1-C2 alkyl, C1-C5 alkoxy, xe2x80x94Cl, xe2x80x94Br, xe2x80x94F, xe2x80x94OCH2Cxe2x95x90OOQ, xe2x80x94OCH2 cyclopentyl, xe2x80x94CH2OCH2-phenyl, saturated and unsaturated 5- and 6-membered rings, saturated and unsaturated 5- and 6-membered rings containing at least one hetero atom wherein the hetero atom is selected from S, N and O,
wherein Q is selected from H and lower alkyl,
Y1 and Y2 are independently selected from xe2x80x94Cl, xe2x80x94Br, xe2x80x94NO2, xe2x80x94Cxe2x89xa1N and xe2x80x94Cxe2x89xa1CH,
with the proviso that where Y1, and Y2 are both xe2x80x94Cl, and R1 is xe2x80x94CH3 or phenyl, then X4 is not xe2x80x94Cl.
xe2x80x9cEffective amountxe2x80x9d means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
xe2x80x9cHalogenxe2x80x9d means fluorine, chlorine, bromine or iodine.
xe2x80x9cHetero atomxe2x80x9d means an atom selected from N, O and S.
xe2x80x9cIC50xe2x80x9d refers to the concentration of a particular compound required to inhibit 50% of a specific measured activity. IC50 can be measured, inter alia, as is described subsequently.
xe2x80x9cAlkylxe2x80x9d denotes a straight-chained or branched saturated aliphatic hydrocarbon. xe2x80x9cLower alkylxe2x80x9d groups denote C1-C6 alkyl groups and include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 2-butyl, pentyl, hexyl, and the like. Generally, lower alkyl is preferably C1-C4 alkyl, and more preferably C1-C3 alkyl.
xe2x80x9cAlkoxyxe2x80x9d denotes xe2x80x94O-alkyl. xe2x80x9cLower alkoxyxe2x80x9d denotes xe2x80x94O-lower alkyl.
xe2x80x9cPharmaceutically acceptable esterxe2x80x9d refers to a conventionally esterified compound of formula I having a carboxyl group, which esters retain the biological effectiveness and properties of the compounds of formula I and are cleaved in vivo (in the organism) to the corresponding active carboxylic acid.
Information concerning esters and the use of esters for the delivery of pharmaceutical compounds is available in Design of Prodrugs. Bundgaard H ed. (Elsevier, 1985). See also, H. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 108-109; Krogsgaard-Larsen, et. al., Textbook of Drug Design and Development (2d Ed. 1996) at pp. 152-191.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of the present invention and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. Chemical modification of a pharmaceutical compound (i.e. drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., H. Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457.
xe2x80x9cPharmaceutically acceptable,xe2x80x9d such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
xe2x80x9cSubstituted,xe2x80x9d as in substituted alkyl, means that the substitution can occur at one or more positions and, unless otherwise indicated, that the substituents at each substitution site are independently selected from the specified options.
xe2x80x9cTherapeutically effective amountxe2x80x9d means an amount of at least one designated compound, that significantly inhibits proliferation and/or prevents differentiation of a human tumor cell, including human tumor cell lines.
Compounds of the present invention as exemplified advantageously show IC50s from about 70 xcex7M to about 100 xcexcM.
The compounds of the present invention are useful in the treatment or control of cell proliferative disorders, in particular oncological disorders. These compounds and formulations containing said compounds may be useful in the treatment or control of solid tumors, such as, for example, breast, colon, lung and prostate tumors.
A therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
The therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage will be adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion.
The compounds of the present invention can be prepared according to the following Schemes. The following definitions are provided as applicable to the synthesis schemes:
V1, V2, V3, V4, V5 are each independently selected from:
Hydrogen,
xe2x80x94OV6,
xe2x80x94SV7,
xe2x80x94NV8V9,
xe2x80x94CONV8V9,
xe2x80x94COOV10,
halogen,
nitro,
trifluoromethyl,
lower alkyl, which optionally may be substituted by V11, and
cycloalkyl;
V1, V2 together may form part of a heterocycle with one or more heteroatoms, which optionally may be substituted by V10.
V2, V3 together may form part of a heterocycle with one or more hetereoatoms, which optionally may be substituted by V10.
Y1, Y2 are each independently selected from:
xe2x80x94Cl,
xe2x80x94Br,
nitro,
cyano; and
xe2x80x94Cxe2x89xa1CH
V, is selected from COV12 and CONV13V14,
V6 is selected from the group of:
hydrogen,
lower alkyl, which optionally may be substituted by V11, and cycloalkyl;
V7 is selected from the group of:
hydrogen, and
lower alkyl;
V8, V9 are each independently selected from the group of:
hydrogen,
lower alkyl, and
cycloalkyl;
V8, V9 together may form part of a heterocycle with one or more hetereoatoms;
V10 is selected from the group of:
hydrogen,
lower alkyl, and
cycloalkyl;
V11 is selected from the group of:
xe2x80x94CONV8V9,
xe2x80x94NV8V9,
xe2x80x94COOV10,
aryl,
halogen,
lower alkoxy,
morpholinyl, and
heterocycles;
V12 is selected from the group of
hydrogen,
lower alkyl,
cycloalkyl,
aryl,
heterocycle, and
heteroaryl;
V13 and V14 are independently selected from the group of
lower alkyl,
cycloalkyl,
lower alkyl substituted by V11; or
V13 and V14 together may form part of a
hetercycle such as morpholine, piperidine, pyrrolidine and piperazine;
The piperazine may be substituted by
lower alkyl,
hydroxyalkyl,
acyl, acyl substituted with hydroxy and amino,
alkylsulfonyl,
CONH2,
CONV8V9,
keto,
hydroxy;
The piperidine may be substituted by
dialkyl amine,
pyrrolidine, or
piperidine. 
A compound of formula 2, a known compound or a compound prepared by known methods, is converted to a compound of formula 3 using hydrogen chloride gas in ethanol over a period of several hours to several weeks. A formula of compound 3 is then reacted with a compound of formula 4 in a solvent such as ethanol, at a temperature of 60 to 100xc2x0 C. to afford a compound of formula 5.
When V is COV12, a compound of formula 5 is reacted with a compound of formula ClCOV12 (a known compound or a compound prepared by known methods) at 0xc2x0 C. to 25xc2x0 C. in the presence a base such as triethylamine to give a compound of formula 1.
When V is CONV13V14(providing that NHV13V14 is a known compound or a compound prepared by known methods), a compound of formula 5 is reacted with phosgene at 0xc2x0 C. in the presence of triethylamine followed by the treatment of a compound of formula HNV13V14 to afford a compound of formula 1. 
As set forth in Scheme II, when V15 substituted piperazines are not commercially available (V15 may be acyl, acyl substituted with hydroxyl, amino, protected amino and sulfonyl), a compound of formula 7 is prepared as follows: a compound of formula 5 is reacted with phosgene and triethylamine followed by the treatment of piperazine to afford a compound of formula 6. A compound of 6 is reacted with V15X to give a compound of formula 7.
As set forth in Scheme III, a compound of formula 8 can be prepared from a compound of formula 6 by the reaction of phosgene and triethylamine followed by the treatment of NHV8V9, a known compound or a compound prepared by known methods. 
The meso-1,2-diamine of formula 4 (Y1=Y2) can be prepared according to the literature procedures (see Jennerwein, M. et al. Cancer Res. Clin. Oncol. 1988, 114, 347-58; Vogtle, F.; Goldschmitt, E. Chem. Ber. 1976,109, 140).
If it is desired to prepare a compound of formula 4 wherein Y1xe2x89xa0Y2, modifications to the existing procedure can be made. An equal molar mixture of the benzaldehydes and meso-1,2-bis-(2-hydroxy-phenyl)-ethane-1,2-diamine can be used to afford a mixture of 1,2-diamines (Scheme IV). Knxc3x6lker, H. J. , et al. Tetrahedron Letters 1998, 39, p. 9407. It was then reacted with di-t-butyldicarbonate in the presence of dimethylaminopyridine to give a compound of formula 9 after HPLC purification. Compound 9 is then converted to a compound of formula 4 by the treatment of hydrobromic acid in hot acetic acid. 
If it is desired to prepare a compound of formula 2 which is not commercially available, many synthetic methods known in the art can be employed. Suitable processes for synthesizing these benzonitriles are provided in the examples. Following schemes illustrate some of these methods.
A compound of formula 11 (V16 can be any suitable group such as V1, V2, V3, V4, or V5) can be prepared by alkylation of a compound of formula 10 with V6X (Xxe2x95x90Cl, Br, I) using conventional methods (scheme V). The phenoxide anion is generated by a base such as cesium carbonate or potassium carbonate. The reaction typically is carried out in refluxing acetone. V6 can also be introduced using Mitsunobu reaction (see for example, Hughes, D. L. Org React. 1992, 42, 335-656). 
A compound of formula 12 (V16 can be any suitable group such as V1, V2, V3, V4, or V5) can be converted into the benzonitrile 13 using literature procedures (Karmarkar, S. N; Kelkar, S. L.; Wadia, M. S. Synthesis 1985, 510-512; Bergeron, R. J. et al. J. Med. Chem. 1999, 42, 95-108). V group can then be introduced using V6X (Xxe2x95x90Cl, Br, I) or Mitsunobu reaction to give the benzonitrile 13 (scheme VI). 
A compound of formula 15 can be prepared by bromination or iodination of phenol 14 (Scheme VII), (V16 can be any suitable group such as V1, V2, V3, V4, or V5). Reaction conditions such as N-bromosuccinamide/tetrahydrofuran or iodine/thallium(I) acetate can be utilized (see for example, Carreno, M. C.; Garcia Ruano, J. L.; Sanz, G.; Toledo, M. A.; Urbano, A. Synlett 1997, 1241-1242; Cambie, R. C.; Rutledge, P. S.; Smith-Palmer, T.; Woodgate, P. D. J. Chem. Soc., Perkin Trans. 1 1976, 1161-4). V5 group can then be introduced using V6X (Xxe2x95x90Cl, Br, I) or Mitsunobu reaction. Methods of converting aromatic halides to the corresponding nitrites are known in the art (see for example, Okano, T.; Iwahara, M.; Kiji, J. , Synlett 1998, 243). Cyanation of the halide 15 (Xxe2x80x2xe2x95x90Br, I) can be accomplished using zinc cyanide with a catalyst such as tetrakis(triphenylphosphine)palladium (0). Solvents such dimethylformamide can be used and the reaction temperature is between 80-110xc2x0 C. 
In scheme VIII, amination of aromatic halide 16 using HNV7V8 and palladium catalyst can be utilized to provide the benzonitrile of formula 17 (see for example, Harris, M. C.; Geis, O.; Buchwald, S. L. J. Org. Chem. 1999, 64, 6019). 
A compound of formula 13 (V16can be any suitable group such as V1, V2, V3, V4, or V5) can be prepared by nucleophilic substitution of 2-halobenzonitrile 18 (scheme IX). (see for example, Xxe2x95x90F: Wells, K. M.; Shi, Y.-J.; Lynch, J. E.; Humphrey, G. R.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1996, 37, 6439-6442; Xxe2x95x90NO2: Harrison, C. R.; Lett, R. M.; McCann, S. F.; Shapiro, R.; Stevenson, T. M. WO 92/03421, 1992). 
To prepare the benzonitrile of formula 21 wherein V1, V2, V3, V4, or V5xe2x95x90OV6, sequential alkylation of the diol 19 with suitable V6X (Xxe2x95x90Cl, Br, I) are used. The bromides 20 are then converted to the nitrites 21 using zinc cyanide and Pd(0) catalyst (scheme X). 
Certain of the following Examples refer to Examples provided in U.S. Provisional application Serial No. 60/341,729 and Serial No. 60/390,876 both entitled CIS-IMIDAZOLINES. The Examples of these Provisional applications are incorporated herein by reference.
The present invention encompasses the following Examples. For structural formulas shown, it is understood that oxygen and nitrogen atoms with available elections have a hydrogen bound thereto, as indicated by compound name.